3-(2-Chloro­ethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

Jerry P Jasinski; Ray J Butcher; Q N M Hakim Al-Arique; H S Yathirajan; B Narayana

doi:10.1107/S1600536809027548

. 2009 Jul 25;65(Pt 8):o1987–o1988. doi: 10.1107/S1600536809027548

3-(2-Chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

Jerry P Jasinski ^a, Ray J Butcher ^b,^*, Q N M Hakim Al-Arique ^c, H S Yathirajan ^c, B Narayana ^d

PMCID: PMC2977208 PMID: 21583662

Abstract

In the title molecule, C₁₁H₁₁ClN₂O, the pyrido[1,2-a]pyrimidine ring system is planar (maximum deviation = 0.0148 Å) and the methyl C and carbonyl O atoms are nearly coplanar to it. The chloroethyl side chain is in a synclinal conformation, nearly orthogonal to the pyrimidine ring, with a dihedral angle between the chloroethyl side chain and the pyrimidine ring of 88.5 (1)°. Weak intermolecular C—H⋯N and C—H⋯Cl hydrogen bonds along with π–π interactions between the pyrimidine and pyridine rings [centroid–centroid distance is 3.538 (2) Å] form a three-dimensional network. The crystal is a racemic twin with a 0.68 (12):0.32 (12) domain ratio. MOPAC AM1 and density functional theory (DFT) theoretical calculations at the B3-LYP/6–311+G(d,p) level support these observations.

Related literature

For related structures, see: Blaton et al. (1995 ▶); Chen & He (2006 ▶); Elotmani et al. (2002 ▶); Jottier et al. (1992 ▶); Koval’chukova et al. (2004 ▶); Peeters et al. (1993 ▶); Ravikumar & Sridhar, (2006 ▶); Yu et al. (2007 ▶). For general background to heterofused pyrimidines, see: Baraldi et al. (2002 ▶); Bookser et al. (2005 ▶); Chen et al. (2004 ▶); La Motta et al. (2007 ▶); Gabbert & Giannini (1997 ▶); Goodacre et al. (2006 ▶); Hossain et al. (1997 ▶); Joseph & Burke (1993 ▶); Nikitin & Smirnov (1994 ▶); Sabnis & Rangnekar (1990 ▶); Wang et al. (2004 ▶); White et al. (2004 ▶). For the synthesis, see: Toche et al. (2008 ▶). For GAUSSIAN03 theoretical calculations, see: Becke (1988 ▶, 1993 ▶); Frisch et al. (2004 ▶); Hehre et al. (1986 ▶); Lee et al. (1988 ▶); Schmidt & Polik (2007 ▶).

Experimental

Crystal data

C₁₁H₁₁ClN₂O
M _r = 222.67
Orthorhombic,
a = 4.2546 (4) Å
b = 11.6274 (10) Å
c = 20.604 (2) Å
V = 1019.27 (17) Å³
Z = 4
Mo Kα radiation
μ = 0.35 mm⁻¹
T = 110 K
0.51 × 0.35 × 0.12 mm

Data collection

Oxford Diffraction Gemini R CCD diffractometer
Absorption correction: multi-scan (CrysAlis RED; Oxford Diffraction, 2007 ▶) T _min = 0.835, T _max = 0.959
4613 measured reflections
3089 independent reflections
2607 reflections with I > 2σ(I)
R _int = 0.054

Refinement

R[F ² > 2σ(F ²)] = 0.065
wR(F ²) = 0.181
S = 1.11
3089 reflections
138 parameters
H-atom parameters constrained
Δρ_max = 0.99 e Å⁻³
Δρ_min = −0.52 e Å⁻³
Absolute structure: Flack (1983 ▶), 1103 Friedel pairs
Flack parameter: 0.32 (12)

Data collection: CrysAlisPro (Oxford Diffraction, 2007 ▶); cell refinement: CrysAlisPro; data reduction: CrysAlisPro; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809027548/ci2827sup1.cif

e-65-o1987-sup1.cif^{(16.6KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809027548/ci2827Isup2.hkl

e-65-o1987-Isup2.hkl^{(151.6KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C5—H5A⋯N2ⁱ	0.95	2.50	3.394 (3)	157
C2—H2A⋯Clⁱⁱ	0.95	2.90	3.559 (3)	128

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

QNMHA thanks the University of Mysore for use of its research facilities. RJB acknowledges the NSF MRI program (grant No. CHE-0619278) for funds to purchase an X-ray diffractometer.

supplementary crystallographic information

Comment

Heterofused pyrimidines exhibit promising antiviral (Hossain et al. 1997), antibacterial (Sabnis & Rangnekar, 1990), anti-AIDS (Joseph & Burke, 1993), and antinociceptive (Bookser et al. 2005) activities. Fused pyrimidines are extensively used in neurology, particularly in the treatment of neurodegenerative disorders such as Parkinson's disease (Baraldi et al. 2002), antianxiety disorders (Goodacre et al. 2006) and depression (Chen et al. 2004). Fused pyrimidines are selective inhibitors for multidrug resistance (MDR) (Wang et al. 2004). A review on the synthesis, chemical and biological properties of pyrido[1,2-a]pyrimidines is described (Nikitin & Smirnov, 1994). Pyrido[1,2-a]pyrimidin-4-one derivatives as a novel class of selective aldose reductase inhibitors exhibiting antioxidant activity has been reported (La Motta et al. 2007). The synthesis and anticonvulsant evaluation of some new 2-substituted-3-arylpyrido[2,3-d]pyrimidinones have also been reported (White et al. 2004). The crystal structures of 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl}-6,7,8,9- tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (risperidone) (Peeters et al. 1993), 3-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (Pirenperone) (Blaton et al. 1995), 5-methyl-2-morpholino-3-p-tolyl-8,9,10,11-tetrahydro-2-benzothieno[2', 3':6,5]pyrido[4,3-d]pyrimidin-4(3H)-one (Chen & He, 2006), 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-2,9- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (Ocaperidone) (Jottier et al. 1992), 2-methyl-3-(3-methyl-1H-pyrazol-5-yl)pyrido[1,2-a]pyrimidin-4-one (Elotmani et al. 2002), 2-methyl-3-chloro-9-hydroxypyrido[1,2-a]pyrimidin-4-one and bis(2-methyl-3-chloro-9-hydroxypyrido[1,2-a]pyrimidin-4-onium) perchlorate (Koval'chukova et al. 2004), 3-(2-chloroethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidin-1-ium chloride (Ravikumar & Sridhar, 2006) and 9-(4-methoxybenzoyl)-1,2,3,4-tetrahydro-6H-pyrido[1,2-a]pyrimidin-6-one (Yu et al. 2007) have also been reported.

The title compound, (I), is an intermediate in the synthesis of risperidone, which is a potent antipsychotic agent, especially useful for treating schizophrenia (Gabbert & Giannini, 1997). In view of the importance of (I), the present paper describes its crystal structure.

The overall molecular geometry of (I), including bond distances and angles, is in good agreement with related structures (Blaton et al. 1995; Jottier et al. 1992; Peeters et al. 1993; Ravikumar & Sridhar, 2006). It consists of a pyridine ring fused to a substituted pyrimidine ring creating a planar ring system (maximum deviation, C1, = -0.0148Å) with the methyl C and carbonyl O atoms nearly coplanar to the pyrimidine ring (Torsion angles C1-C9-C7-C8 = 177.6 (3)° ; C2-N1-C1-O = -2.5 (4)° (Fig. 1). The sum of the angles aroumd N1 is 360.0 (5)° indicating sp² hybridization. The chloroethyl side chain is in a synclinal (-sc) conformation (C1—C9—C10—C11 torsion angle = -86.6 (3)°), nearly orthogonal to the pyrimidine ring, with a dihedral angle separation between the C10/C11/Cl group and the pyrimidine ring of 88.5 (1)°.

While no classic hydrogen bonds are observed, a weak intermolecular hydrogen bond interaction exists between atom C5 from the pyridine ring and N2 from a nearby pyrimidine ring (Table 1 and Fig. 2). In addition, a weak intermolecular interaction between atom C2 from the pyrimidine ring and Cl from the substituted pyrimidine group also occurs, each influencing crystal packing and, therefore, resulting in a three-dimensional network (Fig. 2). In addition, π-π interactions between N1/C1/C9/C7/N2/C6 (centroid Cg1) and N1/C2-C6 (centroid Cg2) rings of molecules at (x, y, z) and (1+x, y, z), with a Cg1···Cg2 distance of 3.538 (2) Å, provide additional stability to the crystal packing. The crystal is a racemic twin with domains of 0.68 (12) and 0.32 (12).

In support of these observations, a MOPAC AM1 (Schmidt & Polik, 2007) and density functional theory (DFT) geometry optimized theoretical calculation (Schmidt & Polik, 2007) with the GAUSSIAN03 program package (Frisch et al. 2004) employing the B3-LYP (Becke 3 parameter Lee-Yang-Parr) exchange correlation functional, which combines the hybrid exchange functional of Becke (Becke, 1988, 1993) with the gradient-correlation functional of Lee, Yang and Parr (Lee et al. 1988) and the 6–311+G(d,p) basis set (Hehre et al. 1986), was performed on (I) utilizing starting geometries taken from the X-ray refinement data. In both calculations the resulting bond distances and angles remained relatively constant. However, the C9—C10—C11—Cl torsion angle decreased by 3.2 (1)° to 175.4 (3)° (MOPAC) and 0.07° to 178.5 (7)° (DFT) and the dihedral angle between the C10/C11/Cl group and the pyrimidine ring decreased by 2.3 (8)° to 86.1 (3)° (MOPAC) and by 8.3 (6)° to 80.1 (5)° (DFT), respectively.

In summary, it is clear that the collection of weak intermolecular hydrogen bond interactions and π-π intermolecular interactions do play a role in stabilizing crystal packing of (I).

Experimental

The title compound was synthesized following the reported procedure (Toche et al. 2008). Pale yellow crystals of compound (I) were obtained by slow evaporation from ethyl acetate solution (m.p. 405–408 K). Analytical data: Found (calculated): C %: 59.28 (59.33); H%: 4.97 (4.98); N%: 12.54 (12.58).